Advancing food allergy research through omics sciences – Genetics of Food Allergy Study

Research Leader:: Prof. Dr. Young-Ae Lee
Institution:: Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft (MDC)

BACKGROUND

Food allergies and other allergic diseases (e. g. eczema, asthma, hay fever) are a growing health problem. According to The International Study of Asthma and Allergies in Childhood (ISAAC) up to 15% of school children and adolescents in Spain are affected, with a third of the patients suffering from a combination of several allergic diseases. It is well-known that children of allergic parents have a much higher risk of developing allergies than children of non-allergic parents.

Many studies demonstrated that heredity (genetics) plays an important role in the development of allergic diseases. However, very little is known about the genes causing food allergy. In contrast to other complex diseases for which there are extremely large study cohorts of hundreds of thousands of individuals with available phenotype and genotype data (e.g. UK Biobank), phenotype data on food allergies is generally unavailable in such cohorts and current genomic cohorts are limited to only hundreds of individuals.

Food allergy (FA) is a complex disease arising from the interaction between multiple genetic and environmental factors. Epidemiological studies indicate that genetic factors contribute substantially to disease expression: The sibling risk of a child with FA to be affected is 5,4-fold increased compared to that of the general population. Moreover, twin studies have estimated the heritability of peanut allergy at 81,6%. Thus understanding the genetic determinants of FA will provide important clues to the underlying molecular mechanisms and will identify potential molecular targets for improved risk assessment, diagnosis and prevention.

Genome-wide association studies (GWAS) have revolutionized our understanding of the genetics of allergic diseases by identifying novel genetic loci and disease-related pathways with high confidence. Important insights from these studies include i) generally small effect sizes (odds ratios, OR, often < 1.3) requiring very large study cohorts to detect them, ii) a large overlap of susceptibility loci involved in different allergic and/or chronic inflammatory diseases, and iii) a localization of most risk variants in non-coding regions pointing to effects on gene regulation rather than effects on protein structure and function.

To date GWAS for FA have been restricted to relatively small sample sizes owing to the difficulty in obtaining a reliable diagnosis. A systematic review of the literature revealed that the point prevalence of self-reported FA was approximately six times higher than the point prevalence of challenge-proven FA, suggesting that over 80% of history-based FA diagnoses cannot be confirmed in an oral food challenge (OFC). Even if the diagnosis was based on reported allergic symptoms plus elevated specific IgE or a positive skin prick test, the prevalence of FA was overestimated by a factor of 3 compared with challenge-proven FA.

The challenge for future genetic studies of FA is to assemble very large study groups of well phenotyped patients with FA for GWAS. Due to insufficient sample size, the genetic analysis of clinical subphenotypes, such as allergies to specific allergens, polyvalent FA, FA severity, FA persistence, etc. have remained mostly unexplored. Furthermore, the identification of rare and/or non-coding variants in FA will require more detailed genomic information including whole genome-sequencing, investigation of DNA modifications, etc.

HYPOTHESIS

This is a hypothesis-free study for identification of genes and biomarkers associated with food allergies and allergic diseases. We hypothesize that food allergies have a large genetic contribution.

OBJECTIVES

The aim of this study is to find and further investigate hereditary factors that contribute to the development of food allergy and other allergic diseases (e.g. eczema, asthma, hay fever) at the population level.

METHODOLOGY (please include Subjects, Ethics, Confidentiality, Return Of Results and Incidental Findings management)

The GCAT cohort will be analyzed both independently and in conjunction with additional samples. GCAT participants will be used as ethnically matched, population-based control subjects of children clinically diagnosed with food allergy at the Hospital Sant Joan de Déu, Barcelona. This new dataset will be analyzed independently and in conjunction with additional study cohorts, including the German Genetics of FA study (GOFA), currently comprising about 1500 cases and >3000 controls.

For the genetic research analyses, we will use present and future genetic methods to detect as much of the genetic variation as possible. The complete experimental and statistical methodology is established in the laboratory of Young-Ae Lee. Our analyses include, among others, genome-wide association studies, whole genome sequence analysis, heritability estimations, genomic risk score calculations, genetic correlations, and omics integrative analyses. All genetic analyses will be conducted for research purposes only.

The genomic cohort (i.e. pseudonymized data + genotyped data) will be only stored within the data infrastructure of the Max Delbrück Center in Berlin-Buch. Such data will be stored within the Lee Lab network within the MDC network. The main copy of the data will reside at the MDC workstation of Dr. Aleix Arnau Soler. Recurrent backups are performed internally at the MDC and managed by an internal IT administrator of Lee Lab within the MDC Berlin-Buch infrastructure following standard MDC protocols. In addition, a copy will be stored in a physical and external hard disk which resides inside the Lee Lab workspace and its exclusive function is to store sensitive data. Such hard disk never leaves neither the Lee Lab workspaces nor MDD Berlin-Buch campus. Only Prof. Dr. Young-Ae Lee and Dr. Aleix Arnau Soler will have rights to access such data. Other researchers at Lee Lab may be granted access by Prof. Dr. Young-Ae Lee to a copy, always within the Lee Lab network, in future. Data security within the Lee Lab network is managed by an internal IT administrator. MDC also have its own IT department that ensures data protection within the MDC Berlin-Buch infrastructure.

This study will be conducted according to the principles of the Declaration of Helsinki (64^th WMA General Assembly, Fortaleza, Brazil, October 2013). This investigation project will follow appropriate approval procedure including the MEC, relevant/competent authorities, and other applicable regulatory requirements. The investigation will not be initiated until approval has been obtained from the MEC and the regulating competent authority. Any additional requirements from ethics/regulatory authority will be followed. Information on subject ID / pseudonym will be completely anonymous.

This study will be conducted according to "Ley 14/2007, de 3 de julio, de Investigación biomédica". (Boletín Oficial del Estado, n° 159, (4-7-2007). España.)

All investigations and studies derived from GCAT data will be submitted for publication into scientific journals of international scope after previous communication with GCAT collaborators (i.e. Rafael de Cid) and its approval.